Crystalline solvate of omeprazole sodium

ABSTRACT

The present invention belongs to the field of pharmaceutical industry and relates to novel crystalline omeprazole sodium ethanol solvate and to the process for its preparation, which acts as intermediary compound to the processes for its conversion into different crystalline forms, first of all to a known omeprazole sodium form A, with low amount of residual solvents, i.e. less than 0.5% by weight of residual solvent. 
     The present invention also relates to novel crystalline omeprazole sodium form E and crystalline omeprazole sodium form F as well to the processes for their preparation as well, both with considerably low levels of residual solvents. 
     Omeprazole sodium form A and both novel crystalline forms omeprazole sodium form E and form F are useful for the treatment of gastrointestinal disorders.

FIELD OF THE INVENTION

The present invention belongs to the field of pharmaceutical industryand relates to a novel crystalline ethanol solvate of omeprazole sodiumsalt. Omeprazole is generic name of(5)-6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazoleused in the treatment of gastrointestinal disorders. Further, theinvention relates to a process for the preparation of crystallineomeprazole sodium ethanol solvate and to the processes for itsconversion into different crystalline forms of omeprazole sodium. Firstof all, to a readily feasible and reproducible process of conversion ofsaid novel omeprazole sodium ethanol solvate to at ambient temperaturestable omeprazole sodium of known crystalline form, hereinafter referredto as omeprazole sodium form A, with low amount of residual solvents.

The present invention relates also to two novel crystalline forms ofomeprazole sodium, hereinafter referred to as omeprazole sodium form Eand omeprazole sodium form F. Further, the present invention relates tothe processes for the preparation of omeprazole sodium form E andomeprazole sodium form F, both with cosiderably low levels of residualsolvents.

Furthermore, the present invention relates to the use of omeprazolesodium form E and omeprazole sodium form F for the treatment of diseasesrelated to gastric acid hypersecretion, and to a pharmaceuticalcompositions containing as active substance omeprazole sodium form E andomeprazole sodium form F.

TECHNICAL PROBLEM

Chemical stability, solid state stability and “shelf life” of an activepharmaceutical ingredient are important properties for a pharmaceuticalactive compound. It is generally known that stability of the activepharmaceutical ingredient among others depends also upon residualsolvents. Therefore, it is highly desirable to provide stable andcrystalline solid form of the active pharmaceutical ingredient with lowlevel of residual solvents, preferably in an industrially simple andreproducible process.

There is a constant need for new solid forms of omeprazole sodium andmethods of their preparation since it has been observed that a number ofdrugs exhibit desirable dissolution characteristics and, in some cases,desirable bioavailability patterns when used in a specific solid form.Moreover, properties such as stability and higroscopicity of polymorphsmay differ.

PRIOR ART

The compound known under chemical name(5)-6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazoleand having the generic name omeprazole is known as a proton pumpinhibitor, which inhibits gastric acid secretion. Omeprazole may be usedfor the treatment of gastric acid related disorders and gastrointestinalinflammatory diseases in mammals and especially in man, including e.g.gastro-esophageal reflux, esophagitis, heartburn, gastritis,hypersecretory conditions (e.g. Zollinger-Ellison, endocrine adenoma),duodenitis, gastric ulcer and duodenal ulcer. Omeprazole is also usefulfor treating infections such as those caused by Heliobacter pylori.Omeprazole and pharmaceutically acceptable salts thereof were firstdescribed in the patent EP-B-5129.

The specific alkaline salts of omeprazole, such as the sodium salt, werefirst described in the patent EP-B-124 495. Omeprazole sodium saltprepared according to examples 1 and 2 of EP-B-124 495 is unstable and amixture of crystal forms and amorphous material. One of the crystalforms present in the mixture is omeprazole sodium form A and is ahydrate with one to two molecules, of which one water molecule isstrongly bound in the crystal structure while the other is easilyremoved by drying. The resulting dried substance containing one stronglybound water molecule is very hygroscopic and absorbs water rapidly undernormal conditions.

Well-defined omeprazole sodium monohydrate salt, hereinafter referred toas omeprazole sodium form B, and preparation thereof is disclosed inU.S. Pat. No. 6,207,188. According to the description omeprazole sodiumform B is a crystalline form exhibiting advantageous properties, such asbeing well-defined, thermodynamically stable, non-hygroscopic and beinga true monohydrate crystal form. In contrary to form B the patentdescribes omeprazole sodium form A as thermodynamically unstable formwhich can under certain storing conditions be completely or partlyconverted to omeprazole sodium form B. U.S. Pat. No. 6,207,188 providesalso a process for the preparation of such unstable omeprazole sodiumform A. Disadvantage of the described process is that it is timeconsuming since it takes more than 3 days to be completed.

US Patent Application Publication US 2004/0224987 A1 discloses similar,although improved process for the preparation of omeprazole sodium formA, which comprises the steps of dissolving omeprazole in an aqueousbase, Na⁺ B⁻ wherein Na donates sodium and B donates hydroxide oralkoxide, ion exchangers, resins which releases sodium cation, at roomtemperature, in an appropriate solvent consisting of C₃-C₇ branched orchained hydrocarbons, C₂-C₇ branched or chained ethers, cyclic ethers,lower fatty acid esters, aliphatic ketone solvents, halogenatedhydrocarbon solvents or nitrile solvents with optionally containingwater, followed by neutralisation of resultant solution by anappropriate anti-solvent in which product is poorly soluble, stirringthe reaction mixture for 0-24 hrs at room temperature, cooling thereaction mixture till the solid mass crystallises, filtering theisolated solid by conventional techniques, accompanied by washing with asolvent as mentioned above, drying the isolated compound at 30° to 70°C., preferably at a temperature of 50° to 60° C. to afford form A ofomeprazole sodium. The resulting omeprazole sodium form A is stated tobe more thermodinamically stable, non-hygroscopic and with permissibleresidual solvents limits. US 2004/0224987 further provides novelcrystalline omeprazole sodium form C and crystalline omeprazole sodiumform D and processes for preparation thereof.

In ES 2023778 a process for production of omeprazole metal salts, suchas the sodium salt, using alkaline salt of active methylene compounds isdisclosed.

Omeprazole salts in amorphous form and a process for the preparationthereof using spray-drying technique are disclosed in WO 01/87831.

The invention described in U.S. Pat. No. 6,262,085 provides6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazoleor pharmaceutically acceptable salts thereof with explanation thatmaking of a salt in solution results in the making of both compounds,having the methoxy group on the benzimidazole ring at the 6- and5-position, due to tautomerization occurring in the solution.

Acetone complexes of sulfoxide compounds or pharmaceutically acceptablesalts thereof of formula (I) are disclosed in patent EP-B-1 000 943,giving the examples for rabeprazole.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a powder X-ray diffraction pattern of omeprazole sodiumethanol solvate.

FIG. 2 shows a powder X-ray diffraction pattern of omeprazole sodiumform A prepared by the process according to the present invention.

FIG. 3 shows a powder X-ray diffraction pattern of omeprazole sodiumform E.

FIG. 4 shows a powder X-ray diffraction pattern of omeprazole sodiumform F.

FIG. 5 shows an IR spectrum of omeprazole sodium ethanol solvate.

FIG. 6 shows an IR spectrum of omeprazole sodium form A prepared by theprocess according to the present invention.

FIG. 7 shows an IR spectrum of omeprazole sodium form E.

FIG. 8 shows an IR spectrum of omeprazole sodium form F.

FIG. 9 shows a differential scanning calorimetry curve (DSC) ofomeprazole sodium ethanol solvate (solid line) and omeprazole sodiumform A (dotted line) as prepared according to the present invention.

DESCRIPTION OF THE INVENTION INCLUDING EXAMPLES

An object of the present invention is to find a novel process forpreparing omeprazole sodium form A with low amount of residual solvents,which would be stable at ambient temperature. Further the object of thepresent invention is directed to a novel crystalline omeprazole sodiumform E and the related process of its preparation and to a novelcrystalline omeprazole sodium form F and related process of itspreparation.

This problem has been solved by the present invention which relates to anovel stable crystalline omeprazole sodium ethanol solvate which is anintermediary compound in the novel process for the preparation of stablecrystalline omeprazole sodium form A and in a processes for thepreparation of novel crystalline omeprazole sodium form E and a novelcrystalline omeprazole sodium form F as well. X-ray powder diffraction(XRPD) is used as a method of differentiating between stable crystallineomeprazole sodium form A, novel stable crystalline intermediateomeprazole sodium ethanol solvate, novel stable crystalline omeprazolesodium form E and novel stable crystalline omeprazole sodium form F.

According to the present invention omeprazole sodium ethanol solvate isprepared by dissolving omeprazole (base) in a solution of NaOH inabsolute ethanol. Mechanical particles are removed from the resultingsolution, e.g. by filtration, and further seeded with crystals ofomeprazole sodium form A to induce crystallisation. The slurry is thenagitated for several hours at ambient temperature and additionally forseveral hours at low temperatures, e.g. from 0° to 5° C., in order toimprove the yield. The precipitated omeprazole sodium form A isseparated, e.g. by filtration or centrifugation, and washed with cooledabsolute ethanol. Omeprazole sodium ethanol wet thus derived is driedunder reduced pressure from 40° to 50° C., preferably at about 45° C. toyield stable anhydrous omeprazole sodium in ethanol solvate form. By theterm “omeprazole sodium ethanol wet” is meant the product obtainedbefore the step of drying under reduced pressure. The term “reducedpressure” generally refers to a pressure of about 10 mbar to about 50mbar.

Omeprazole sodium ethanol solvate prepared by the process underanhydrous conditions according to the present invention contains fromabout 8 to about 11% by weight (as determined by gas chromatography) ofresidual ethanol incorporated in the crystalline lattice. Thisincorporated ethanol defines ethanol solvate crystalline form ofomeprazole sodium and cannot be removed upon further drying. The waterassay in omeprazole sodium ethanol solvate determined bythermogravimetric analysis or by Karl Fischer, techniques known per se,was found to be less than 0.5% by weight, what corresponds to anhydrousproduct.

Omeprazole sodium form A is highly soluble in water and as such suitablefor parenteral formulations, providing an opportunity for physicians totreat patients suffering from gastroesophageal reflux disease (GERD) whoare unable to take oral therapy. In this way, parenteral formulations ofnovel omeprazole sodium ethanol solvate with residual solventincorporated in the solid would be pharmaceutically unacceptable, but isuseful as valuable intermediate for the preparation of crystalline formsof omeprazole sodium, substantially free of incorporated solvents. Theterm substantially free means less than 0.5% by weight of residualsolvent, i.e. ethanol.

Thus, in order to obtain a hydrate of omeprazole sodium in the specificcrystalline form, namely known form A, it is necessary to exchangeethanol that is incorporated in the crystalline lattice of omeprazolesodium ethanol solvate with molecules of water. We have surprisingly andunexpectedly found out that the exchange may be conveniently performedby digesting novel omeprazole sodium ethanol solvate in a mixture ofnon-solvent and water. The term digesting is understood as a method inwhich a product is suspended in a solvent in which it is insoluble orpoorly soluble, herein referred as non-solvent, then small amount ofwater is added and a resulting suspension is stirred for a definedperiod of time.

More specifically, omeprazole sodium ethanol solvate is converted toomeprazole sodium form A by the process of digesting the crystals ofomeprazole sodium ethanol solvate in a mixture of suitable non-solventand water. By the term suitable solvent is meant a non-solvent selectedfrom the group consisting of diisopropyl ether, tert-butyl methyl ether,diethyl ether, ethyl acetate and acetonitrile, preferably diisopropylether, at the temperature range from 0° to 20° C., preferably from 50 to10° C., for a period of 30 minutes to 10 hours, more preferably forabout 4 hours. After completing the reaction the precipitated omeprazolesodium form A is then recovered, e.g. by filtration or centrifugation,in excellent yield and dried under conditions which avoid degradation ofthe desired product, e.g. at 40° to 50° C. under reduced pressure for 10to 24 hours.

In another aspect of the present invention, instead of omeprazole sodiumethanol solvate also omeprazole sodium ethanol wet may be used in thevariant process of digesting but under condition that it is previouslywashed with a suitable amount of non-solvent, selected from the groupconsisting of diisopropyl ether, tert-butyl methyl ether, diethyl ether,ethyl acetate and acetonitrile, preferably diisopropyl ether, beforedigesting it in a mixture of non-solvent and water. By the term suitableamount of non-solvent is meant the amount that will wash the residualethanol from about 20% by weight to about 10% by weight, thus obtainingomeprazole sodium ethanol solvate. The whole process for the preparationof crystalline sodium form A starting from omeprazole (base) and usingthe washing of omeprazole sodium ethanol wet becomes thus less timeconsuming by avoiding the drying before the step of digesting.

Since omeprazole sodium in the crystalline form A is a hydrate with oneto two moles of water per one mole of omeprazole sodium, at least about10% to about 20% of water by weight regarding omeprazole sodium,preferably about 10% of water by weight, is needed in the process ofdigesting to obtain stable omeprazole sodium crystalline form A and withlow amount of residual solvent.

The volume ratio in the mixture non-solvent:water used in the digestingprocess according to the present invention is in the range from 40:1 to100:1, more preferably in the range from 60:1 to 80:1.

The level of residual solvents present in omeprazole sodium form Aprepared by the process according to the present invention determined bygas chromatography, technique known per se, was found to be below 0.5%by weight limit.

The water assay in crystalline omeprazole sodium form A prepared by theprocess according to the present invention determined bythermogravimetric analysis or by Karl Fischer, techniques known per se,was found to be from 6 to 8% what corresponds to one mol of water beingbound in the crystal, i.e. 4.7%, while the other molecules of water areonly absorbed on the crystal.

The present invention thus describes the process for the preparation ofomeprazole sodium form A which comprises dissolving omeprazole (base) insolution of NaOH in absolute ethanol, inducing the crystallisation byseeding with crystals of omeprazole form A, isolation of the novelintermediate, i.e. anhydrous omeprazole sodium ethanol solvate, which isfurther converted into hydrate of omeprazole sodium, in the crystallineform A, by the process of digesting in the mixture of non-solvent andwater. Accordingly, the present invention for the preparation ofomeprazole sodium form A uses the conditions which are convenient toperform on an industrial scale and operationally safe. Another advantageof the process is that it is simple, economic and fast.

Additionally, we have found that omeprazole sodium form A prepared bythe process according to the present invention is stable, substantiallyfree of any other forms of omeprazole sodium, i.e. without detectableamounts of any other forms of omeprazole sodium, easy to handle and maybe stored over appreciable period of time, without exhibiting asignificant change in the physico-chemical characteristics e.g. chemicalcomposition, hygroscopicity, solubility and crystalline form.

The stability of omeprazole sodium form A obtained by the processes ofthe present invention may be determined by standard protocol forcharacterisation of stability of a pharmaceutically active substance(EU: Adopted by CPMP, March 2003, issued as CPMP/ICH/2736/99—“Committeefor proprietary medical products; Note for Guidance on ICH Q1A (R2)Stability testing guidelines: Stability testing of new drug substancesand products”). Packed omeprazole sodium form A were aged for a definiteperiod of time (1 month, 3 months, 6 months) under accelerated conditionof aging (at a temperature of 40° C. and 75% relative humidity which isa standard accelerated condition for stability testing of pharmaceuticalformulations) and/or stress condition of aging (at temperature of 60° C.which is a standard stress condition for stability testing ofpharmaceutical active substances). Determination of absorbance measuredaccording to PhEur method (PhEur 3 Suppl 2000), was used as criterionfor evaluation of the sample quality during stability testing. It haspreviously been shown that measurement of absorbance is a more sensitivemethod for monitoring the process of omeprazole sodium decompositionthan, for example, detection of present impurities using chromatographicmethods (PhEur 3 Suppl 2000).

Omeprazole sodium ethanol solvate and omeprazole sodium form A, preparedaccording to the simple and improved process of the present inventionwere analysed using X-ray powder diffraction (XRPD) pattern and gave thediffractograms depicted in FIG. 1 and FIG. 2. The main peaks, withpositions and relative intensities, have been extracted from thediffractograms and given below in the Table 1. The positions of thepeaks (d values) in both cases were determined according to the standardprocedure (Kug, H. P. & Aleksander, L. E., 1974). The relativeintensities are less reliable and instead of numerical values thefollowing definitions are used:

Relative Intensity Definition 25-100 very strong 10-25  strong 3-10medium 1-3  weak <1 very weak

Some additional peaks with low intensities found in the diffractogramshave been omitted from Table 1.

Additionally, novel omeprazole sodium ethanol solvate of the presentinvention have IR spectrum of FIG. 5 and the differential scanningcalorimetry curve (DSC) of FIG. 9 (solid line).

Crystalline omeprazole sodium form A prepared according to the presentinvention have IR spectrum of FIG. 6 and the differential scanningcalorimetry curve (DSC) of FIG. 9 (dotted line).

TABLE 1 Positions and intensities of the major peaks in the XRPD ofomeprazole sodium ethanol solvate and omeprazole sodium form A preparedaccording to the present invention omeprazole sodium ethanol solvateomeprazole sodium form A d value/Å relative intensity d value/Å relativeintensity 15,659 very strong 15,651 very strong 8,246 weak 7,910 weak7,913 strong 7,554 weak 7,262 weak 7,251 very strong 6,876 weak 6,861medium 6,663 weak 6,660 medium 6,515 weak 6,491 medium 5,441 weak 5,383weak 5,376 medium 5,221 medium 5,222 strong 4,717 weak 4,710 medium4,552 weak 4,390 weak 4,416 medium 4,307 weak 4,308 medium 4,180 weak4,185 medium 4,073 weak 4,074 medium 3,948 medium 3,945 very strong3,844 weak 3,839 strong 3,759 weak 3,754 medium 3,620 weak 3,621 strong3,527 medium 3,551 strong 3,499 strong 3,426 weak 3,428 medium 3,385weak 3,311 weak 3,323 medium 3,270 weak 3,269 medium 3,220 medium 3,126medium 3,130 medium 3,043 weak 3,046 medium 3,027 weak 3,027 medium2,918 medium 2,926 strong 2,886 medium 2,839 medium 2,841 medium

On the basis of the presented analytical data it seems that omeprazolesodium ethanol solvate and omeprazole sodium form A represent similarcompounds but close examination of both diffractograms shows there arepeaks in one diffractogram that are not present in the other and viceversa, and also differences in intensities among peaks are huge which isnot due to preferential orientation. Obviously, omeprazole sodiumethanol solvate and omeprazole sodium form A, as one being solvate andthe other hydrate, they crystallize in different crystal structures thushaving different physicochemical properties, including melting point,solubility, hygroscopicity, stability.

In another aspect of the present invention we have surprisingly andunexpectedly found two novel crystalline polymorphic forms of omeprazolesodium, namely omeprazole sodium form E and omeprazole sodium form F,which are disclosed herein.

Simple processes for conversion of omeprazole sodium ethanol solvateinto omeprazole sodium form E and omeprazole sodium form F which aresubstantially free from any other forms of sodium salts of omeprazole,such as omeprazole sodium form A and with considerably low levels ofresidual solvents are also disclosed herein.

The above term “any other form” is meant anhydrous, hydrates, solvatesand amorphous material, including polymorphs disclosed in the prior art.

The two novel crystalline forms, omeprazole sodium form E and omeprazolesodium form F are characterized by their X-ray powder diffraction (XRPD)patterns as shown in FIG. 3 and FIG. 4 and by IR spectra as shown inFIG. 8 and FIG. 9, respectively. These characteristic are not exhibit byany other form of omeprazole sodium known in the prior art.

Omeprazole sodium form E is characterised by very strong X-raydiffraction peak at about 5.33±0.2 degrees 2-theta. It is furthercharacterized by peaks of strong relative intensities at about 10.66,16.02, 19.01, 26.29 and 33.47±0.2 degrees 2-theta; and with peaks ofmedium relative intensities at about 13.48, 14.98, 19.89, 21.42. 23.02,25.47, 30.43 and 31.47±0.2 degrees 2-theta.

Omeprazole sodium form F is characterized by very strong X-raydiffraction peak at about 6.52±0.2 degrees 2-theta. It may further becharacterized by a peak of strong relative intensity at about 19.63±0.2degrees 2-theta; and with peaks of medium relative intensities at about13.79, 15.76, 18.47, 20.38, 21.50, 22.50, 23.22, 24.28 and 25.96±0.2degrees 2-theta.

Further object of the present invention are simple processes for thepreparation of two novel crystalline forms omeprazole sodium form E andomeprazole sodium form F, respectively.

We have unexpectedly found that by recrystallisation of omeprazolesodium ethanol solvate from suitable solvent, selected from the groupconsisting of acetone, ethyl methyl ketone, 4-methyl-2-pentanone orcyclohexanone a novel omeprazole crystalline forms of omeprazole sodiumwith low content of residual solvents may result.

Thus, omeprazole sodium ethanol wet or dried omeprazole sodium ethanolsolvate as intermediary compounds prepared as described above (see alsoexample 1 and example 2) may be converted into novel omeprazole sodiumform E or novel omeprazole sodium form F by recrystallization from abovedescribed selected solvent, preferably at room temperature. Which one ofthe two novel crystalline forms of omeprazole sodium may be obtaineddepends on the selection of the above described solvent used inrecrystallisation of the intermediate. Precipitated crystals of novelomeprazole sodium forms are collected, e.g. by filtration, and driedunder reduced pressure at about 45° C.

Thus, recrystallisation of omeprazole sodium ethanol solvate fromacetone or cyclohexanone gives omeprazole form E, as anhydrous product,with the amount of organic solvent lower than 0.1% by weight.

Recrystallisation of omeprazole sodium ethanol solvate from4-methyl-2-pentanone yields omeprazole sodium form F, as anhydrousmaterial, with a little bit higher level of residual solvent, i.e. about1% by weight.

Recrystallisation of omeprazole sodium ethanol solvate from ethyl methylketone gives a mixture of both forms, namely omeprazole sodium form Eand omeprazole sodium form F, as anhydrous material, with amount ofresidual solvents around 0.3% by weight.

Residual solvents in omeprazole sodium form E and omeprazole sodium formF may be determined by gas chromatography.

The water assay in omeprazole sodium form E and omeprazole sodium form Fmay be determined by thermogravimetric analysis or by Karl Fischer,techniques known per se.

Omeprazole sodium form E and omeprazole sodium form F are easy tocharacterize because they exist in a well-defined crystalline state.Both said novel forms of omeprazole sodium may be prepared in a simpleand reproducible manner.

Omeprazole sodium form E and omeprazole sodium form F are stablecompounds under special conditions (stored under nitrogen atmosphere)since both are hygroscopic and they will absorb up to about 7% by weightof water from air, depending on the relative humidity of the air. Bothsaid novel forms of omeprazole sodium may be adversely converted toknown crystalline omeprazole sodium form A by such absorption of waterfrom air.

EP-B-1 000 943 describes also a process for preparation of acetonecomplex of sodium salt of sulfoxide compounds (e.g. rabeprazole sodium)by recrystallisation in acetone or in a mixture of acetone with solvent,e.g. n-hexane, isopropyl ether, toluene and ethyl acetate.

According to NMR studies as well as GC (gas chromatography) analysisperformed we have proved that no complex was formed in the process ofrecrystallisation of omeprazole sodium ethanol solvate in acetone.

It is known that omeprazole is useful proton pump inhibitor and can beused for the control of gastric acid secretion in mammals and especiallyin man. In particular, omeprazole sodium form A, as well as novelomeprazole sodium form E and omeprazole sodium form F may be used forprevention and the treatment of gastric-acid related conditions,including for example, reflux esophagitis, gastritis, duodenal ulcer,non ulcer dyspepsia, upper gastrointestinal bleeding, stress ulceration,gastronomas, in patients on NSAID therapy, and pre-operative andpost-operative to prevent aspiration of gastric acid. Further,omeprazole sodium form A, as well as both novel omeprazole forms E and Fmay be useful in the treatment of psoriasis and in the treatment ofHelicobacter infections and diseases related to these.

The preparation of a pharmaceutical compositions containing omeprazolesodium form A and/or form E and/or form F, substantially free ofresidual solvents and pharmaceutically acceptable excipients is alsodisclosed herein. The pharmaceutical compositions are suitable for oraland parenteral administration. The most suitable route of administrationas well magnitude of a therapeutic dose of omeprazole sodium accordingto the invention in any given case will depend on the nature andseverity of the disease to be treated. The dose and dose frequency mayalso vary according to the age, body weight, and response of theindividual patient. In general, a suitable dose of the active ingredientis within the range of 10 mg to 80 mg daily, preferably between 20 to 40mg of total daily dosage. Dosage forms include capsules, tabletes,dispersions, solutions, suspensions, emulsions, gels, powders.

Methods

X-Ray Powder Diffraction: Siemens d-5000 powder diffractometer usingreflection geometry and CuKa radiation in the range from 2 to 37° 2θ instep of 0.03° 2θ, integration time was 5 second per step and the slitswere set to 20 mm (variable divergence) and 0.6 mm (receiving).

FT-Infrared: Nicolet Nexus FTIR spectrofotometer using potassium bromidepellet method with 16 scans and 2 cm⁻¹ resolution, scanning from 400 to4000 cm⁻¹.

Diffraction Scanning Calorimetrv: Mettler Toledo DSC822^(e) differentialscanning calorimeter, the sample (4-8 g) was placed in an unsealedaluminium pan with one hole and heated at 3° K/min in the temperaturerange from 70° C. to 170° C. in the air atmosphere.

Gas Chromatography: column RTX 624, 30 m×0.53 mm; T_(starting)=40° C.,T_(gradient)=40° C./min till 200° C., 5 min; injector: splitless, T=140°C.; detector: FID, T=200° C.; mobile phase: helium, 5 psi; T_(oven)=80°C.; sample: 115 mg/mL DMA (N,N-dimethyl acetamide).

The invention is illustrated by the following Examples:

Example 1 Preparation of Omeprazole Sodium Ethanol Wet from Omeprazole

Into solution of NaOH (36.5 g, 0.91 mol) in absolute ethanol (650 mL)omeprazole (300 g, 0.87 mol) is added. The slurry is stirred for 20minutes at ambient temperature. The resulting solution is filteredthrough a layer of celite and charcoal on a Büchner funnel of porosityB4. The solution is seeded with omeprazole sodium form A (1 g) toinitiate the crystallisation and stirred at ambient temperature for 8hours. The formed slurry is stirred for additional 8 h at thetemperature range from 0° to 5° C. and the product is filtered off andwashed with absolute ethanol (100 mL), cooled to 5° C. to yield 289 g ofomeprazole sodium ethanol wet.

Example 2 Preparation of Omeprazole Sodium Ethanol Solvate

289 g of omeprazole sodium ethanol wet obtained as described in Example1 was dried at reduced pressure at 45° C. overnight to yield 245 g ofomeprazole sodium ethanol solvate.

Water content % (w/w by TgA)<0.5%.

Powder XRDP, IR (in KBr) and DSC are shown in FIGS. 1, 5 and 9 (solidline).

Example 3 Preparation of Omeprazole Sodium Form A

289 g of omeprazole sodium ethanol wet from Example 1 is additionallywashed three times with 300 mL of diisopropyl ether and transfered intoa 5 L reactor. Diisopropyl ether (3 L) and water (45 mL) were added andthe slurry intensively stirred for 4 hours at 5° C. Crystals areseparated by filtration and dried under reduced pressure at 45° C.overnight to yield 220 g of omeprazole sodium form A.

Water content % (w/w by TgA)=7.5%

Powder XRDP, IR (in KBr) and DSC are shown in FIGS. 2, 6 and 9 (dottedline).

Example 4 Preparation of Omeprazole Sodium Form E

15 g of dried omeprazole sodium ethanol solvate from Example 2 isdissolved in acetone (150 mL). After stirring the solution overnight atambient temperature the resulting product is filtered off and driedunder reduced pressure at 45° C. overnight to yield 11.5 g of the titleproduct.

Water content % (w/w by TgA)<0.5%.

Powder XRPD and IR (in KBr) are shown in FIGS. 3 and 7.

Example 5 Preparation of Omeprazole Sodium Form F

20 g of dried omeprazole sodium ethanol solvate from Example 2 isdissolved in 4-methyl-2-pentanone (400 mL). After stirring the solutionovernight at ambient temperature the resulting product is filtered offand dried under reduced pressure at 45° C. overnight to yield 16.4 g ofthe title product.

Water content % (w/w by TgA)<0.5%.

Powder XRDP and IR (in KBr) are shown in FIGS. 4 and 8.

1. A Crystalline omeprazole sodium ethanol solvate having an X-raypowder diffraction (XRPD) pattern containing peaks substantially as setout in Table
 1. 2. The Crystalline omeprazole sodium ethanol solvateaccording to claim 1, wherein it provides an X-ray powder diffractionpattern substantially in accordance with FIG.
 1. 3. The Crystallineomeprazole sodium ethanol solvate according to claim 1, wherein thecontent of ethanol in said compound amounts from about 8% to about 11%by weight.
 4. The Crystalline omeprazole sodium ethanol solvateaccording to claim 1, wherein the content of water in said compound isless than 0.5% by weight.
 5. (canceled)
 6. (canceled)
 7. A process forthe preparation of crystalline omeprazole ethanol solvate as defined inclaims 1-4, wherein said process comprises the step of: a) dissolvingomeprazole in a solution of NaOH in absolute ethanol; b) allowing thesolution to crystallize; c) removing the obtained crystals by filtrationor centrifugation, d) drying the crystals of omeprazole sodium wet thusderived; e) isolating the anhydrous omeprazole sodium ethanol solvatethus obtained.
 8. (canceled)
 9. A process for the preparation ofcrystalline omeprazole sodium form A wherein crystalline omeprazolesodium ethanol solvate as defined in any of claims 1-4 is used and,wherein said process comprises the steps of: a) Optionally washing theomeprazole sodium ethanol wet with non-solvent selected from the groupconsisting of diisopropyl ether, tert-butyl methyl ether, diethyl ether,ethyl acetate and acetonitrile; b) digesting the anhydrous crystallineomeprazole ethanol solvate as defined in claim 1-4 in a mixture ofnon-solvent and selected from the group consisting of diisopropyl ether,tert-butyl methyl ether, diethyl ether, ethyl acetate and acetonitrile.water; c) after completing the reaction thus obtained omeprazole sodiumform A is isolated; d) drying omeprazole sodium form A thus obtained.10. (canceled)
 11. (canceled)
 12. The process as defined in claim,wherein the volume ratio in the mixture non-solvent:water in thedigesting process is in the range from 40:1 to 100:1.
 13. (canceled) 14.The process as defined in claims 6-7, wherein the content of residualsolvent present in omeprazole sodium form A is less than 0.5% by weight.15. (canceled)
 16. The crystalline omeprazole sodium form E, wherein itprovides an X-ray powder diffraction pattern with peaks 5.33, 10.66,13.48, 14.98, 16.02, 19.01, 19.89, 21.42, 23.02, 25.47, 26.29, 30.43,31.47 and 33.47±0.2 degrees 2-theta.
 17. The crystalline omeprazolesodium form E according to claim 16,9 wherein it provides an X-raydiffractogram pattern containing peaks in accordance with FIG.
 3. 18.(canceled)
 19. The crystalline omeprazole sodium form E according toclaim 16, wherein the content of residual solvent in said compound isless than 0.1% by weight.
 20. (canceled)
 21. The crystalline omeprazolesodium F, wherein it provides an X-ray powder diffraction pattern withpeaks 6.52, 13.79, 16.76, 18.47, 19.63, 20.38.21.50, 22.50, 23.22, 24.28and 25.96±2-theta.
 22. The crystalline omeprazole sodium form Faccording to claim 21, wherein it provides an X-ray powder diffractionpattern containing peaks in accordance with FIG.
 8. 23. (canceled) 24.The crystalline omeprazole sodium form F according to claim 21, whereinthe content of residual solvent in said compound is about 1% by weight.25. A process for the preparation of crystalline omeprazole sodium formE as defined in claims 16 17 and 19, wherein said process comprises thesteps of: a) anhydrous omeprazole sodium ethanol solvate as defined inany of the claims 1-4 is recrystallized from the solvents selected fromthe group consisting of acetone and cyclohexanone; b) after completingthe reaction thus obtained omeprazole sodium form E is isolated, c)drying omeprazole sodium form E thus obtained.
 26. A process for thepreparation of crystalline omeprazole sodium form F as defined in claims21-22 and 24, wherein said process comprises the steps of: a) anhydrousomeprazole sodium ethanol solvate as defined in any of the claims 1-4 isrecrystallized from 4-methyl-2-pentanone; b) after completing thereaction thus obtained omeprazole sodium form F is isolated; c) dryingomeprazole sodium form F thus obtained.
 27. A pharmaceutical formulationcomprising omeprazole sodium which is selected from form E as defined inclaim 16, 17 and 19, or form E as defined in claims 21, 22 and 24 orethanol solvate as defined in claims 1-4 in admixture with apharmaceutically acceptable excipient.
 28. (canceled)
 29. (canceled) 30.(canceled)